5-(alpha-amino benzyl)-10,11-dihydro-and 5h-dibenzo(a,d)cyclohepten-5-ols and the salts thereof

ABSTRACT

SUBSTITUTED BENZYL-10,11-DIHYDRO AND CORRESPONDING 10,11-UNSATURATED DIBENZOCYCLOHEPTENOLS, E.G. 5-(A-AMINO BENZYL) - 10,11 - DIHYDRO - 5H-DIBENZO(A,D)CYCLOHEPTEN5-OL, USEFUL AS DIURETICS, PREPARED FROM ASERIES OF REACTIONS STARTING WITH A DIBENZO-CYCLOHEPTENONE AND LITHIATED N-BENZYL BENZAMIDES.

United States Patent ABSTRACT OF THE DISCLOSURE Substituted benzyl-10,11-dihydro and corresponding 10,11-unsaturated dibenzocycloheptenols, e.g. 5-(a-amino benzyl) 10,11 dihydro 5H-dibenzo[a,d]cyclohepten- 5-ol, useful as diuretics, prepared from a series of reactions starting with a dibenzo-cycloheptenone and lithiated N-benzyl benzamides.

This invention pertains to novel substituted benzyl dibenzoeycloheptenols, acid addition salts thereof, and processes for their preparation.

More particularly, the compounds of this invention may be represented by the formula:

H H X R-L 1 R 5 W E E0 (EH NHz R (I) where X represents CHz-CHg or CH=CH, and R represents H or halo of atomic weight about 19-3 6.

The compounds of Formula I may be prepared from the compounds of Formula II in accordance with the following reaction scheme:

drogenated at about 40-60 lbs. per sq. inch, preferably about 50 lbs. per sq. inch, in alcoholic solvents, preferably loweralkanols such as ethanol, at a temperature of about 20-70 C., conveniently room temperature. The reaction may be allowed to proceed until about 1 equivalent of hydrogen is absorbed. In the event the hydrated form of the final product (I) is obtained, such form may be converted to the unhydrated form by conventional techruques.

The compounds of Formula II may be prepared from the compounds of Formula HI according to the following reaction scheme:

R R -r Ho eG 11H R In A n H /X R I R n X E E0 -Q 1 111 R (II) where X and R are as defined above Compounds II are thus prepared by treating Compounds HI with a metal hydride reducing agent such as lithium aluminum hydride in ether solvents such as ethyl ether or tetrahydrofuran at a temperature of about 50- C., conveniently at reflux temperature of the system, for a period of about 1-8 hours, preferably for about 3-5 hours.

Compounds III are obtained according to the following reaction scheme:

where X and R are as defined above.

In accordance with this process for making Compounds III, Compounds IV and V are condensed in inert solvents such as ethers, e.g. diethyl ether or tetrahydrofuran, or hydrocarbons such as hexane, heptane and the like, optionally in inert atmosphere, e.g. nitrogen, at a temperature of about -10 C. to +10 0., preferably about 0 C., for about l-8 hours, preferably about 3-5 hours. The resulting adduct is then subjected to conventional hydrolysis to obtin the Compounds III.

Compounds V are prepared from the corresponding benzyl benzamides of the formula where R is as defined above by lithiating the latter by use of lower alkyl or aryl lithium compound such as n-butyl lithium in inert hydrocarbon or ether solvents such as those mentioned above useful in the condensation of Compounds IV and V. The lithiation is preferably performed at the same temperatures and at the same periods of time as indicated above respecting said condensation. The dilithiated Compound V is normally not recovered from the lithiation process but is used directly in the preparation of Compounds III.

In each of the above reactions, the particular temperature and solvent utilized is not critical. Additionally, except where otherwise indicated, the products of each of said reactions are recovered by conventional techniques such as crystallization, filtration, trituration and the like.

Certain of the compounds of Formulas IV and VI are known and may be prepared according to methods disclosed in the literature. The compounds of Formulas IV and VI not specifically disclosed may be prepared from methods analogous to those in the literature from known compounds.

Certain of the compounds of Formulas I, II and HI exist in racemic form or in the form of optically active isomers. The separation and recovery of the respective isomers may be readily accomplished employing conventional techniques, and such isomers are included within the scope of the invention.

Compounds I and II may exist in the form of their acid addition salts. Said salts and their respective free bases may be converted from one to the other by conventional techniques, and are chemically interchangeable for purposes of the above-described processes.

The compounds of Formula I are useful because they possess pharmacological properties in animals such as mammals. In particular, the compounds may be used as diuretics as indicated by their activity in rats orally administered -50 rug/kg. and dogs intravenously administered 5 mg. /kg. of animal body weight. The rats are unanesthetized male Wistar rats (240-360 gm.) which are fasted overnight. Six animals are used for each of the test substance, chlorothiazide and control groups. These compounds are suspended in 1.5% carboxymethyl cellulose for oral administration. The concentration is adjusted so that 1 ml./ 100 gms. body weight provides the desired dosage. The animals also receive 2 ml./100 gm. body weight of saline (p.o.) to insure adequate hydration (total volume equals 3 ml./ 100 gm. body weight). Data of test agents are compared with those obtained from a chlorothiazide group (25 mgJkg.) and a control group (1 ml. 1.5 carboxymethyl cellulose, 2 ml. saline/100 gm. body weight). Complete bladder evacuation is effected at zero time. Urine is collected for three hours in metabolism cages. Volumes are recorded and samples are taken for electrolyte (Na+ and K+) measurement by flame photom etry. The dog test animal is anesthetized and urine outflow is determined by measuring the outflow from the catheterized ureters with the aid of a standard dropcounter.

For such usage, the compounds of Formulas I may be combined with a pharmaceutically acceptable carrier or adjuvant, and may be administered orally in such forms as tablets, capsules elixirs, suspensions and the like, or parenterally in the form of an injectable solution or suspension. The dosage will vary depending upon the mode of administration utilized and the particular compounds employed.

As indicated above, the compounds of Formula I may be similarly administered in the form of their non-toxic pharmaceutically acceptable acid addition salts. Such salts possess the same order of activity as the free base and are included within the scope of the invention. Representative of such salts are the mineral acid salts, such as hydrochloride, hydrobromide, sulfate, phosphate and the like and the organic acid salts, such as the succinate, benzoate, acetate, p-toluenesulfonate, benzensulfonate and the like.

As noted above, the compounds of Formulas I, II, and III exist as optical isomers. In some cases, greater pharmacological activity or other beneficial attribute may be found for a particular isomer and in such instances administration of such isomer may be preferred.

In general, satisfactory results are obtained when the compounds I are administered orally at a daily dosage of from about 4-400 mg./kg. of animal body weight, prefery given i divided doses, two to four times a day or in sustained release form. For most large mammals (e.g. primates) the total daily dosage is from about 300-3,000 mg. per day. Dosage forms suitable for internal use comprise -from about 754,500 mg. of active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier or diluent.

A tablet containing mg. of S-(a-amino benzyl)-l0, 11 dihydro-5H-dibenzo[a,d] cyclohepten-S-ol hydrochloride hemihydrate and 225 mg. of lactose is prepared by conventional techniques and is useful in effecting diuresis in accordance with this invention at a dosage of one capsule two to four times a day.

EXAMPLE 1 5- (N-benzoyl-e-amino benzyl) -10, 1 l-dihydro-SH- dibenzo[a,d]cyclohepten-S-ol v To a flask equipped with a stirrer, dropping funnel, condenser and gas inlet tube maintained under a nitrogen atmosphere there is added at room temperature 42.2 g. (0.2 mole) of N-benzyl benzamide in 450 ml. of dry tetrahydrofuran. The flask is immersed in an ice bath and cooled to an internal temperature of 5C. Stirring is initiated and 275 ml. of 1.6 M n-butyl lithium (0.44 mole) in hexane is added dropwise in ca. 1 hour maintaining the temperature below 8 C. The resulting blueblack mixture is stirred 1 hour at room temperature, cooled to an internal temperature of 5 C. and 45.7 g. (0.22 mole) of 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-0ne in 200 ml. dry ether is added in ca. 1 hour maintaining the temperature below 8 C. The reaction mixture is stirred 2 additional hours at 0 C. and then poured onto 1 liter of ice-water. The layers are separated and the organic phase washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated in vacuo to give a solid that is purified by trituration with methylene chloride-ether (1:1) to give S-(N-benzoyl-u-amino benzyl)-10,1 1-dihydro-5H-dibenzo[a,d]cyclohapten-S-ol; M.P. 198-200" C.

When the above described process is carried out and in place of N-benzyl benzamide there is used N-p-chlorobenzyl benzamide, there is obtained through the corresponding dilithiated intermediate 5-(N-benzoyl-a-amino-pchlorobenzyl)-10,l1 dihydro 5H dibenzo[a,d]cyclohepten-S-ol.

When the above detailed process is carried out and in place of 10,11-dihydro5H-dibenzo[a,d]cyclohepten-S-one there is used (a) 5H-dibenzo[a,d]cyclohepten-S-one, or (b) 10,11-dihydro-7-chloro-5H-dibenzo [a,d] cyclohepten- S-One' there is obtained through the corresponding dilithiated intermediate (a) 5-(N-benzoyl-a-amino benzyl)5H-dibenzo[a,d] cyclohepten-S-ol, or

(b) S-(N-benzoyl-a-amino benzyl)-7-chloro-l0,ll-dihydro-SH-dibenzo [a,d] cyclohepten-S-ol, respectively.

EXAMPLE 2 5- N-benzyl-a-amino benzyl -10, l l-dihydro-SH-dibenzo [a,d] cyclohepten-S-ol hydrochloride To a suspension of 3.95 g. (0.104 mole) of lithium aluminum hydride and 200 ml. of dry tetrahydrofuran under nitrogen is added 22 g. (0.052 mole) of S-(N- benzoyl-m-amino benzyl)-10,l l-dihydro-SH-dibenzo [a,d] cyclohepten-S-ol as a solid in portions. The resulting mixture is refluxed for 3 hours, cooled to 0 C. and quenched by the addition ethyl acetate and water. The resulting mixture is dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue is dissolved in ether and treated with gaseous HCl and the resulting solid filtered and recrystallized from methylene chloride-ether (1: 1) to give S-(N-benZyl-a-amino benzyl)- 10,1l-dihydro-5H-dibenzo [a,d] cyclohepten-S 01 hydrochloride, M.P. 197-205 C.

When the above process is carried out and in place of 5- (N-benzoyl-a-amino benzyl)-10,11-dihydro-5H dibenzo [a,d] cyclohepten-S-ol there is used (a) 5-(N-benzoyl-u-amino-p-chlorobenzyl)-10,11 dihydro-5H-benzo[a,d] cyclohepten-S-ol,

(b) 5-(N-benzoyl-a-amino benzyD-SH-dibenzo [a,d] cyclohepten-S-ol, or

(c) S-(N-benZOyI-a-amino benzyl)-7-chloro-10,11 dihydro-5H-dibenzo[a,d] cyclohepten-S-ol,

there is obtained (a) 5-(N-benzyl-u-amino-p-chlorobenzyl)-10,1l-dihydro- SH-dibenzo [a,d] cyclohepten-S-ol hydrochloride,

(b) 5- (N-benzyl-a-amino benzyl) -5H-dibenzo [a,d] cyclohepten-S-ol hydrochloride, or

(c) 5- N-benzyl-a-amino benzy1)-7-chloro-10,1l-dihydro- SH-dibenzo [a,d] cyclohepten-S-ol hydrochloride, respectively.

EXAMPLE 3 5-(u-amino benzyl)-l0,1l-dihydro-SH-dibenzo[a,d]cyclohepten-S-ol hydrochloride hemihydrate (a) 5-(N-benzyl-u-amino-p-chlorobenzyl)-10, 1 l-dihydro- SH-dibenzo [a,d] cyclohepten-S-ol hydrochloride,

(b) 5-(N-benzyl-u-amino benzyl)-5H-dibenzo[a,d]cyclohepten-S-ol hydrochloride, or

(c) 5-(N-benzyl-u-amino benzyl)-7-chloro-10,1l-dihydro- 5H-dibenzo[a,d] cyclohepten-S-ol hydrochloride there is obtained (a) S-(u-amino-p-chlorobenzyD-IO,1l-dihydro 5H dibenzo [a,d]cyclohepten 5 01 hydrochloride hemihydrate,

(b) S-(a-amino benzyl)-5H-dibenzo[a,d]cyclohepten-S-ol hydrochloride hemihydrate, or

6 (c) 5-(a-amino benzyl)-7-chloro-10,1l-dihydro-SH dibenzo [a,d] cyclohepten-S-ol hydrochloride hemihydrate, respectively.

What is claimed is: 1. A compound of the formula I NH: R where X represents CH -CH or CH=CH, and R represents H or halo of atomic weight about 19-36.

or a pharmaceutically acceptable acid addition salt thereof.

2. The compound of claim 1 which is 5-(a-amino benzyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-S-ol.

3. A compound of the formula where X and R are as defined in claim 1 or an acid addition salt thereof.

4. The compound of claim 3 which is 5-(N-benzyl-uamino benzyl)-10,1 1-dihydro-5H-dibenzo[a,d] cyclohepten-S-ol.

References Cited UNITED STATES PATENTS 3,639,423 2/1972 Winter et a1. 260-5709 X ROBERT V. HINES, Primary Examiner U.S. Cl. X.R. 

